Mixed lineage kinase domain like pseudokinase

Mixed lineage kinase domain like pseudokinase (MLKL) is a protein that in humans is encoded by the MLKL gene. [5]

MLKL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2MSV, 4M67, 4MWI
Identifiers
Aliases	MLKL, hmixed lineage kinase domain-like, mixed lineage kinase domain like pseudokinase
External IDs	OMIM: 615153 MGI: 1921818 HomoloGene: 77416 GeneCards: MLKL
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q23.1 Start 74,671,855 bp[1] End 74,700,960 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 E1 Start 111,311,797 bp[2] End 111,338,177 bp[2]
Gene ontology Molecular function • nucleotide binding • GO:0001948 protein binding • ATP binding • protein kinase binding • protein kinase activity • identical protein binding • signal transducer activity • GO:0032403 macromolecular complex binding • protein serine/threonine kinase activity • JUN kinase kinase kinase activity Cellular component • cytoplasm • cytosol • cell membrane • membrane Biological process • GO:0060554, GO:0060555 necroptosis • protein homotrimerization • programmed cell death • protein phosphorylation • GO:0007243 intracellular signal transduction • cell surface receptor signaling pathway • MAPK cascade • activation of JNKK activity • activation of JUN kinase activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	197259	74568
Ensembl	ENSG00000168404	ENSMUSG00000012519
UniProt	Q8NB16	Q9D2Y4
RefSeq (mRNA)	NM_001142497 NM_152649	NM_029005 NM_001310613
RefSeq (protein)	NP_001135969 NP_689862	NP_001297542 NP_083281
Location (UCSC)	Chr 16: 74.67 – 74.7 Mb	Chr 8: 111.31 – 111.34 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis.

Influence in diseases

High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]. Some reports have linked it to unusual variants of multiple sclerosis[6]

See also

• Necroptosis
• Cell death

References

1. GRCh38: Ensembl release 89: ENSG00000168404 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000012519 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Mixed lineage kinase domain like pseudokinase". Retrieved 2017-12-31.
6. Faergeman, S.L., Evans, H., Attfield, K.E. et al. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death Dis 11, 303 (2020). https://doi.org/10.1038/s41419-020-2494-0

Further reading

• Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, Genest J (2010). "Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects". Eur. J. Hum. Genet. 18 (3): 342–7. doi:10.1038/ejhg.2009.157. PMC 2824775. PMID 19844255.
• Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012). "Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase". Cell. 148 (1–2): 213–27. doi:10.1016/j.cell.2011.11.031. PMID 22265413.
• Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG (2012). "Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis". Proc. Natl. Acad. Sci. U.S.A. 109 (14): 5322–7. doi:10.1073/pnas.1200012109. PMC 3325682. PMID 22421439.
• Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W, Xia Z, Han J (2013). "Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling". J. Biol. Chem. 288 (23): 16247–61. doi:10.1074/jbc.M112.435545. PMC 3675564. PMID 23612963.
• Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka B, Shelton JW, Petrova AV, Warren MD, Pantazides BG, Gandhi K, Kowalski J, Kooby DA, El-Rayes BF, Staley CA, Adsay NV, Curran WJ, Landry JC, Maithel SK, Yu DS (2013). "Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma". Cancer. 119 (17): 3148–55. doi:10.1002/cncr.28144. PMC 4389890. PMID 23720157.
• Murphy JM, Lucet IS, Hildebrand JM, Tanzer MC, Young SN, Sharma P, Lessene G, Alexander WS, Babon JJ, Silke J, Czabotar PE (2014). "Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL". Biochem. J. 457 (3): 369–77. doi:10.1042/BJ20131270. PMID 24219132.
• Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG (2014). "Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis". Nat. Cell Biol. 16 (1): 55–65. doi:10.1038/ncb2883. PMID 24316671.
• Pierdomenico M, Negroni A, Stronati L, Vitali R, Prete E, Bertin J, Gough PJ, Aloi M, Cucchiara S (2014). "Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation". Am. J. Gastroenterol. 109 (2): 279–87. doi:10.1038/ajg.2013.403. PMID 24322838.
• Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (2014). "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3". Mol. Cell. 54 (1): 133–146. doi:10.1016/j.molcel.2014.03.003. PMID 24703947.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.